JP2002531454A - Process for preparing paroxetine hydrochloride propan-2-ol solvate - Google Patents

Abstract

  (57) [Summary] A crystalline habit modified crystalline paroxetine hydrochloride propan-2-ol solvate, which more easily desolvates to form an anhydrate, is obtained from a solution of paroxetine hydrochloride in propan-2-ol with strong insolubility. Under nation conditions or in a continuous crystallizer or in an apparatus for seeding paroxetine hydrochloride solvate or anhydrate, especially Form A anhydrate.

Description

DETAILED DESCRIPTION OF THE INVENTION

TECHNICAL FIELD The present invention relates to the preparation of pharmaceutically active compounds and intermediates thereof, and to the use of the active compounds in therapy. Specifically, the present invention relates to a novel process for preparing paroxetine hydrochloride propan-2-ol solvate and its use for preparing the crystalline anhydrous form of paroxetine hydrochloride.

BACKGROUND OF THE INVENTION Antidepressants and medicaments having anti-Parkinsonian properties are disclosed in US Pat. No. 3,912,743.
And U.S. Pat. No. 4,007,196. Of particular interest among the disclosed compounds is paroxetine, ie, 4- (4'-
It is the (-)-trans isomer of fluorophenyl) -3- (3 ', 4'-methylenedioxyphenoxymethyl) piperidine. This compound, as its hydrochloride, is used in therapy, especially in the treatment and prevention of depression, obsessive-compulsive disorder (OCD) and panic disorder. Paroxetine hydrochloride is available as crystalline hemihydrate (Becham Group EP-
A-02223403) and various crystalline anhydrous forms (see Smith Klein Bee Cham WO 96/24595). WO 96/24595 describes the preparation of paroxetine hydrochloride propan-2-ol solvate, a useful intermediate for preparing paroxetine hydrochloride anhydrate Form A. When prepared by crystallization from anhydrous propan-2-ol in a conventional manner, paroxetine hydrochloride propan-2-ol solvate has very poor stirring properties and is very difficult to isolate, wash and dry.

The desolvation of paroxetine hydrochloride propan-2-ol solvate is described in WO 96/25
495 and EP0812827A1. From these publications,
Obviously, desolvation in a vacuum oven is a slow and difficult step. Furthermore, when operating on a scale of more than a few grams, the time and temperature required for substantially complete desolvation are very long and high. For example,
EP 0812827 A1 shows that a product containing still more than 2% of propan-2-ol is obtained after drying for 1 week at 80 ° C. on a scale of 180 g and the residual propane
It states that the temperature must be raised to 110 ° C. to reduce the -2-ol to about 0.1%. Prolonged operation is undesirable for industrial production due to the expense associated with container occupancy, and high temperatures result in product decomposition and phase transition. Another undesirable feature of existing methods is that the product tends to crystallize in a heavy matte form, which is very difficult to stir, move and filter. For example, a seed crystal was added at 48 ° C. to a glass-lined reactor containing a vigorously stirred solution of 160 kg of paroxetine hydrochloride in 160 liters of propan-2-ol. The whole content begins to become a viscous crystalline mass, opening the man-way, allowing the mixture to be stirred and the product to be collected by hand so that the product can be collected. Had to be removed. Thus, it is clear that the current method is not suitable for large-scale production of paroxetine hydrochloride.

DISCLOSURE OF THE INVENTION [0004] The present invention provides a form of paroxetine hydrochloride that is more readily desolvated than paroxetine hydrochloride propan-2-ol solvate prepared by conventional methods.
It provides a method of preparing a 2-ol solvate, that is, a method more suitable for commercial production. According to one aspect of the present invention, there is provided crystalline paroxetine hydrochloride, which comprises obtaining a solution of paroxetine hydrochloride in propan-2-ol and crystallizing paroxetine hydrochloride propan-2-ol solvate under strong insonation conditions. A salt propan-2-ol solvate is provided. Advantageously, the insonation is performed during the slow cooling through the metastable zone and is maintained while cooling to ambient temperature. These conditions result in a freshly formed nucleus of continuous flux, easy to stir, wash and filter, and surprisingly, a conventionally crystallized paroxetine hydrochloride propan-2-ol solvent. Crystallization of the crystal habit modified paroxetine hydrochloride propan-2-ol solvate is more easily desolvated than the solvate. Suitably, the crystallization is provided with a titanium alloy resonance horn with one or more high intensity ultrasound probes, for example, capable of coupling acoustic energy to the crystallization medium at a frequency of 20 kHz, and the acoustics of the road. Performed in a vessel equipped with a device that modulates the output according to parameters. Insonation may be intermittent or limited to a portion of the device, or may be interrupted if sufficient nuclei have formed.

In another aspect of the present invention, rapid crystallization of dense flux into newly generated nuclei is achieved by causing rapid crystallization in a continuous flow crystallizer. Can be achieved. Suitably, two liquid streams, for example a solution of paroxetine hydrochloride in propan-2-ol, and an anti-solvent such as hexane or heptane are combined, or the single solvent stream is rapidly cooled. Or by subjecting a stream of saturated solvent to insonation, or by combining some or all of these techniques. When two streams are combined, nucleation and crystallization take place in the reaction zone, which can be changed from individually designed stirred mixers to simple Y-tubes.

According to another aspect of the invention, a solution of paroxetine hydrochloride in propan-2-ol is prepared from a solution of paroxetine hydrochloride in the presence of a dense flux nucleus provided by seeding. A method is provided for crystallizing a habit modified paroxetine hydrochloride propan-2-ol solvate. Suitable seed crystals include a wide range of paroxetine hydrochloride solvates, such as pyridine, acetic acid, p-xylene, N, N'-dimethylformamide, chloroform, dichloromethane, dichloroethane, acetonitrile, propan-1-ol, ethanol, Obtained from solvates containing propan-2-ol, acetone, tetrahydrofuran or 1,4-dioxane, or from "A" form anhydrous. Advantageously, the seeding is carried out at an elevated temperature using ultrafine powdered paroxetine hydrochloride anhydrate or solvate. The seed should preferably be less than 30 microns in length and have an average particle volume of less than 120 cubic microns. The addition of seed crystals is preferably carried out within the metastable zone, thus 6-8%
At concentrations, the preferred temperature for crystallization is 40-70 ° C, more preferably 55-65 ° C, and optimally 58-62 ° C.

[0007] The effect of external seeding can be significantly increased by very vigorous stirring. This is because the abrasion of the large seed crystal produces another nucleus and increases the flux of a suitable nucleus. In some cases, sufficient flux nuclei can be obtained with only particularly vigorous stirring, but crystallization vessels are not conventionally used for crystallization of paroxetine hydrochloride propan-2-ol solvate, This operation is not considered to be effective if the vessel is not actually filled with seed crystals. Suitable devices include stirrers designed to operate at high torque at high shear rates and optimal hydrodynamically designed vessels, including the use of baffles and bladed stirrers.

[0008] These operations of crystallizing the newly generated nucleus flux modify the crystal habit of the resulting crystals into a form that allows for more effective crystal desolvation. Moreover,
The operation can control the crystallization, where the product is effective and without the use of special equipment and without the formation of dense and non-stirable zones in the crystallization equipment. It can be continuously stirred. A suitable concentration of paroxetine hydrochloride in propan-2-ol is between 4 and 40.
One part by volume, preferably 8 to 15 parts by volume, more preferably 10 to 14 parts by volume of propan-2-ol. Preferably, propan-2-ol is in an anhydrous form to suppress the formation of paroxetine hydrochloride hemihydrate.

The preparation of crystalline paroxetine hydrochloride anhydrate for use as a seed crystal in one of several methods of the invention is described in WO 96/24595. A suitable method for preparing paroxetine hydrochloride in propan-2-ol for use in the method of the present invention is described in U.S. Patent Nos. 4,091,196 and 4,721,723.
Nos. 4,902,801, 4861893 and 5039803. The crystallization may be supplemented by conventional methods such as cooling or removal of the solvent by evaporation or distillation, in addition to the methods described above. The crystalline paroxetine hydrochloride propan-2-ol solvate obtained by the method of the present invention has a different crystalline form from the hitherto known products. This new product forms another aspect of the present invention.

One property that the new form differs from the previously known forms is the particle size distribution and the average particle volume. Conventionally prepared paroxetine hydrochloride propan-2-ol solvate crystals are large and long crystals, most of which are typically greater than 300 microns in length and have a length to width ratio of 300 microns. In the form of crystals larger than 40: 1 and, according to laser light scattering, have a volume of 20,000 cubic microns or more. Conversely, in the novel form of paroxetine hydrochloride propan-2-ol solvate, the majority of the material is crystals shorter than 100 microns long, preferably smaller than 75 microns, more preferably smaller than 50 microns. The length to width ratio is less than 20: 1, preferably less than 15: 1, more preferably less than 10: 1 and has a volume of less than 5000 cubic microns, preferably less than 2500 cubic microns;
More preferably, the crystals are less than 3000 cubic microns. The materials of the present invention have one, two or all three of these desired properties.

[0011] In the course of the study, the inventors have found that one particular crystallographic axis is critical for the rapid desolvation of paroxetine hydrochloride propan-2-ol solvate. Thus, in another aspect of the present invention, the monoclinic system, Miller indices (0,1,0) at P2 ₁ space group and

Embedded image A habit modified paroxetine hydrochloride propan-2-ol solvate is provided, wherein the average distance of the crystal planes characterized by is minimized, preferably less than 100 microns.

Paroxetine hydrochloride propan-2-ol solvate having these properties is
It has been found that paroxetine hydrochloride propan-2-ol solvate previously prepared can be more easily processed and desolvated. The crystallization operation includes, if desired, washing and drying, if desired, to isolate the crystals and remove surface solvents. However, in order to obtain paroxetine hydrochloride anhydrate, especially Form A anhydrate, it is advantageous to use a crystalline solvate as the seed material for the desolvate. Thus, in a further aspect, the present invention provides a method for preparing paroxetine hydrochloride, comprising heating the crystalline propan-2-ol solvate obtained by the method of the invention to remove bound propan-2-ol. Provides a method for producing anhydrate. The desolvation operation is conveniently carried out in an oven, preferably under vacuum, suitably for about 6 hours.
It is performed by heating at a temperature of 0 ° C.

[0013] The resulting anhydride may optionally have less than 3%, preferably less than 1%, more preferably less than 0.5%, and most preferably less than 0.1% propan-2-ol. May be contained. Advantageously, the crystalline anhydrate is Form A anhydrate of paroxetine hydrochloride. The crystalline paroxetine hydrochloride anhydrate obtained according to the present invention is described in EP-A-022.
3403 or WO96 / 00477. Therapeutic uses of paroxetine hydrochloride anhydrate of the present invention include alcoholism, anxiety, depression, obsessive-compulsive disorder (OCD), panic disorder, chronic pain, obesity, senile dementia,
It encompasses migraine, heavy eating, anorexia, blush fear, premenstrual syndrome (PMS), adolescent depression, alopecia, dysthymia and substance abuse, and is hereinafter referred to as "disorder".

The anhydrates obtained according to the invention are optimally applied for the treatment of depression, OCD and panic disorders. Compositions made in accordance with the present invention are generally suitable for oral administration, but soluble formulations for parenteral administration are also within the scope of the present invention. The composition will usually be 1 to 200 mg, more usually 5 to 100 mg, for example 10, 12.5 mg, calculated on a free base basis, for a human patient.
, 15, 20, 25, 30 or 40 mg, such as 10-50 mg, of a unit dose of the composition containing the active ingredient. Most preferably, unit doses contain 20 mg of active ingredient calculated on a free base basis. Such a composition comprises:
Normally, the active ingredient is in the range of 5 to 400 mg calculated on the free base, based on the free base, usually 1 to 6 times a day, for example 2, 3 or 3 times a day. It is administered four times. Most preferably, this unit dose is administered once a day. Preferred unit dosage forms include tablets or capsules, including formulations suitable for controlled or delayed release.

[0015] The compositions of the present invention can be formulated by common mixing operations such as blending, filling and compacting. Carriers suitable for use in the present invention include diluents, binders,
Disintegrating agents, coloring agents, flavoring agents and / or preservatives are included. These substances can be used in a conventional manner, for example, in a manner similar to that used for already marketed antidepressants. Specific examples of the pharmaceutical composition include EP-B-02223403 and U.S. Pat.
007196, wherein the anhydrous product of the present invention can also be used as an active ingredient.

Accordingly, the present invention also provides: a pharmaceutical composition for the treatment or prevention of a disorder, comprising paroxetine hydrochloride anhydrate obtained according to the invention and a pharmaceutically acceptable carrier; a medicament for the treatment or prevention of a disorder. Use of paroxetine hydrochloride anhydrate obtained according to the invention for the manufacture; and administration of an effective or prophylactic amount of paroxetine hydrochloride anhydrate obtained according to the invention to a person suffering from one or more disorders A method of treating a disorder.

(Examples) The following examples of the present invention will be described. In these examples, drying was performed under standard conditions for comparison. Paroxetine hydrochloride propane-2 normally prepared
-All solvates contain about 6% propan-2-ol under these drying conditions (60 ° C for 20 hours). Paroxetine hydrochloride with less residual propan-2-ol for commercial use can be obtained by extending the drying time or increasing the drying temperature.

Comparative Example A solution of paroxetine hydrochloride (10 g) in propan-2-ol (170 ml) was heated to reflux under a nitrogen atmosphere and then cooled to room temperature. After 4 hours, the crystalline product was collected by filtration. The material was dissolved by heating at 60 ° C. under vacuum for 20 hours. Yield 8.98 g (propan-2-ol content; 5.6%). Heating under vacuum for a further 72 hours reduced the propan-2-ol content to 3.1%.

Example 1 Paroxetine hydrochloride propan-2-ol solvate (100 g) and propan-2-ol (800 ml) were placed in a 1 liter jacketed vessel equipped with a mechanical stirrer and a high intensity ultrasound probe. Was. The mixture was stirred under a nitrogen atmosphere and heated to 75 ° C. to give a clear solution, which was then cooled. When the temperature of the solution reached 70 ° C., insonation (frequency 20 kHz, amplitude 12 microns) was started. At 65 ° C., the solution began to cloud and this temperature was maintained for 10 minutes with continued insonation. The mixture was then cooled to ambient temperature and continued insonation for 45 minutes. The product is collected by filtration,
It was dried at 60 ° C. under reduced pressure for 20 hours. The product weighs 81.5 g (propane-2)
-All content 1.5% by weight, needles 10-50 microns in length, no aggregation)
Met. Particle size by laser light scattering: More than 50% of the material was less than 700 cubic microns.

Example 2 Paroxetine hydrochloride propan-2-ol solvate (68 g) and propan-2-ol (925 ml) are placed in a 1 liter jacketed vessel equipped with a mechanical stirrer and a high intensity ultrasound probe. Was. The mixture was stirred under a nitrogen atmosphere and heated to 65 ° C. to give a clear solution. Insonation (frequency 20
kHz, amplitude 12 microns) and allowed the solution to cool. At 59 ° C., the solution turned cloudy and this temperature was maintained for 10 minutes with continued insonation. The suspension was cooled to 40 ° C. and continued insonation for 20 minutes, then cooled to ambient temperature without further insonation. The product was collected by filtration and dried at 60 ° C. under reduced pressure for 20 hours. The product weighs 60.7 g (
The propan-2-ol content was 2.8% by weight, needles 5-100 microns in length, no aggregation). Particle size by laser light scattering: More than 50% of the material was less than 1150 cubic microns.

Example 3 A solution of paroxetine free base (120 g) in propan-2-ol (800 ml) was placed in a 1 liter jacketed vessel equipped with a mechanical stirrer and a high intensity ultrasound probe. The mixture was stirred at ambient temperature under a nitrogen atmosphere to initiate insonation (frequency 20 kHz, amplitude 12 microns). A solution of hydrogen chloride in propan-2-ol (5-6N, 65 ml) was added over 30 minutes, during which time the mixture was continuously insonated for an additional 30 minutes. The product was collected by filtration and dried at 60 ° C. under reduced pressure for 20 hours. The weight of the product was 118 g (propan-2-ol content 2.3% wt / wt).

Example 4 A solution of paroxetine hydrochloride (4.4 g) in propan-2-ol (70 ml) was heated to reflux under argon, then cooled to 60 ° C. and ground to a fine powder with vigorous stirring. Paroxetine hydrochloride anhydrate Form A (0.25 g) was treated with seed crystals. Rapid crystallization occurred, propan-2-ol (30 ml) was added, and the white crystalline solid formed was filtered. The product was filtered, washed with propan-2-ol (15 ml) and dried at 60 ° C. for 20 hours to give paroxetine hydrochloride containing 2.8% by weight of propan-2-ol.

Example 5 A solution of paroxetine hydrochloride (5.17 g) in propan-2-ol (70 ml) was heated to reflux under argon and then cooled to 60-63 ° C. Then, with vigorous stirring, paroxetine hydrochloride anhydrate Form A (0.1 g
) Was added. Rapid crystallization occurs and the precipitate is stirred for 30 minutes, filtered, washed with propan-2-ol, dried at 60 ° C. for 20 hours and paroxetine containing 2.7% by weight of propan-2-ol The hydrochloride was obtained.

Example 6 (−)-trans-N-phenoxycarbonyl-4- (4′-fluorophenyl) -3- (
A mixture of 3 ", 4" -methylenedioxyphenoxymethyl) piperidine (25 g) and potassium hydroxide flakes (22.5 g) in toluene (375 ml) was heated at reflux for 3 hours under a nitrogen atmosphere, and the mixture was then cooled to 20%. Allowed to cool to -30 ° C. Water (250 ml) was added and the organic layer was separated, dried over magnesium sulfate and filtered. The filtrate obtained was evaporated to an oil, then redissolved in propan-2-ol (50 ml) and evaporated again. Then, the oily substance was added to propane-2-
Redissolved in all (200 ml), warmed to 60-67 ° C. and added a solution of hydrogen chloride in propan-2-ol (5-6N, 15 ml). Stir very vigorously,
Nucleation was initiated, during which the temperature was reduced in steps to 55-60 ° C over 30 minutes and then to 40-45 ° C over 1 hour. The product obtained is collected by filtration, washed with propan-2-ol (30 ml), dried under reduced pressure at 60 ° C. for 20 hours, and paroxetine hydrochloride (1.1% by weight of propan-2-ol containing 12% by weight). .
5 g) were obtained. Microscopic particle size: Most crystals were less than 100 micron in length, without agglomeration, and the ratio of length to width was about 7: 1.

──────────────────────────────────────────────────続 き Continuation of front page (81) Designated country EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE ), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CR, CU, CZ, DE, DK, DM, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID , IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72 Inventor David Alan Jones United Kingdom, Thienne 11.9 A.N., Kent, Tonbridge, Near Lee, Old Powder Mills, Smithkline Beechham Pharmaceuticals F-term (reference) 4C063 AA01 BB08 CC81 DD10 EE01 4C086 AA01 AA03 AA04 BC21 GA02 GA07 GA15 GA20 MA01 MA04 NA14 ZA02 ZA12

Claims (29)

[Claims] 1. A crystalline paroxetine hydrochloride, characterized in that a solution of paroxetine hydrochloride in propan-2-ol is obtained and the paroxetine hydrochloride propan-2-ol solvate is crystallized under strong insonation conditions. A method for obtaining a salt propan-2-ol solvate. 2. The method of claim 1 wherein the insonation occurs during slow cooling through the metastable region and is maintained during cooling to ambient temperature. 3. The method according to claim 1, wherein the crystallization is performed by coupling one or more high-intensity ultrasonic probes with acoustic energy having a frequency of 20 kHz and an amplitude of 12 microns or more to the crystallization medium. 3. A method according to claim 1 or 2, wherein the method is carried out in a vessel equipped with a titanium alloy resonance horn made possible and equipped with a device for modulating the output according to the acoustic parameters of the road. 4. The method of claim 1, 2 or 3, wherein the insonation is interrupted intermittently or partially on the device, or interrupted when sufficient nuclei have formed. 5. A crystalline paroxetine hydrochloride propane-2-ol, in which a solution of paroxetine hydrochloride in propan-2-ol is obtained and the paroxetine hydrochloride propan-2-ol solvate is crystallized in a continuous flow crystallizer. A method to obtain an all solvate. 6. The crystallization is effected by combining a solution of paroxetine hydrochloride in propan-2-ol with a stream of two liquids such as an anti-solvent such as hexane or heptane. The described method. 7. The method of claim 5, wherein the crystallization is caused by rapid cooling of a single solvent stream or by insonation of a saturated solvent stream. 8. The method according to claim 5, wherein the crystallization takes place in a reaction zone such as a stirred mixer or a Y-tube. 9. A solution of paroxetine hydrochloride in propan-2-ol is obtained, and paroxetine hydrochloride propan-2-ol solvate is crystallized in the presence of a crystallization nucleus supplied by adding a seed crystal. , Crystalline paroxetine hydrochloride propane-2
-A method of obtaining an all solvate. 10. A seed crystal comprising pyridine, acetic acid, p-xylene, N, N′-dimethylformamide, chloroform, dichloromethane, dichloroethane, acetonitrile, propan-1-ol, ethanol, propan-2-ol, acetone, tetrahydrofuran or 10. The method of claim 9, wherein the method is obtained from paroxetine hydrochloride solvate with 1,4-dioxane or from form "A" anhydrate. 11. The method according to claim 9, wherein the seed crystal is ultrafine powdered. 12. The micronized seed crystal according to claim 9, 10 or 11, wherein the seed crystal consists mainly of crystals having a length of less than 30 microns or an average particle volume of less than 120 cubic microns. Method. 13. The method according to claim 9, wherein the seed crystal is added in a metastable region.
Or the method of 12. 14. Seeding and crystallization at 40-70 ° C., preferably 5 ° C.
The process is carried out at a temperature of 5 to 65 ° C, optimally 58 to 62 ° C.
The method described in. 15. The method according to claim 1, wherein the nucleation is increased by very vigorous stirring.
15. The method according to any one of items 14 to 14. 16. A solution of paroxetine hydrochloride in propan-2-ol is obtained.
Crystalline paroxetine hydrochloride propan-2-ol characterized by producing crystallization nuclei by stirring it very vigorously in the vessel already used for the production of paroxetine hydrochloride propan-2-ol solvate A method of obtaining a solvate. 17. The apparatus of claim 16, wherein the apparatus includes a stirrer designed to operate at high shear rate, high torque, and an optimally hydrodynamically designed vessel, including the use of a baffle and bladed stirrer. Method. 18. A crystalline paroxetine hydrochloride propan-2-ol solvate having a modified crystal habit obtainable by the method according to claim 1. Description: 19. Many of the products from the 50 wt% of the paroxetine hydrochloride propan-2-ol solvate, monoclinic, Miller indices at P2 ₁ space group (0
, 1,0) and A process according to claims 1 to 17 for preparing paroxetine hydrochloride propan-2-ol solvate, wherein the distance between the crystal faces having the following is less than 100 microns. 20. More than 50% by weight of the paroxetine hydrochloride propan-2-ol solvate has a length of less than 100 microns, preferably less than 75 microns, more preferably 50 microns A crystalline paroxetine hydrochloride propan-2-ol solvate, wherein the crystal habit is modified, wherein the crystal is less than. 21. More than 50% by weight of the paroxetine hydrochloride propan-2-ol solvate has a length to width ratio of less than 20: 1, preferably less than 15: 1, more preferably Crystalline paroxetine hydrochloride propan-2-ol solvate wherein the crystal habit is modified, wherein the crystal is less than 10: 1. 22. More than 50% by weight of the paroxetine hydrochloride propan-2-ol solvate has a volume of less than 5000 cubic microns, preferably less than 2500 cubic microns, more preferably less than 1000 cubic microns. A crystalline paroxetine hydrochloride propan-2-ol solvate, wherein the crystal habit is modified. About 23. Many of the products from the 50 wt% of the paroxetine hydrochloride propan-2-ol solvate, monoclinic, Miller indices (0,1,0) at P2 ₁ space group and Embedded image A crystalline paroxetine hydrochloride propan-2-ol solvate, wherein the crystal habit is modified, wherein the distance between crystal faces is less than 100 microns. 24. Paroxetine by heating the crystalline paroxetine hydrochloride propan-2-ol solvate obtained by the method according to claim 1 to remove the bound propan-2-ol. A method for preparing a crystalline anhydrate of a hydrochloride. 25. A method for treating or preventing a disorder, comprising: paroxetine hydrochloride anhydrate obtained by the method according to claim 1; and a pharmaceutically acceptable carrier. Pharmaceutical composition. 26. Use of paroxetine hydrochloride anhydrate obtained by the method according to claim 1 for the manufacture of a medicament for treating or preventing a disorder. 27. An effective or prophylactic amount of paroxetine hydrochloride anhydrate obtained by the method of claim 1 to 17 or 19, which is administered to a person suffering from one or more disorders. How to treat a disorder. 28. Less than 75%, preferably less than 50%, of the standard compared to paroxetine hydrochloride propan-2-ol solvate crystallized conventionally under standard drying conditions A more easily desolvated paroxetine hydrochloride propan-2-ol solvate, which retains less, more preferably less than 25%, of propan-2-ol. 29. Paroxetine hydrochloride propane-claim as claimed in any of the above claims or prepared by a process as claimed in the above claims.
A method for drying a 2-ol solvate.